DESCRIPTION (provide by applicant) The goal of this application is to support the candidate's development in patient-orientated research. This will be done through a program combining didactic teaching, mentoring, and scientific research focusing on the pharmacokinetics of ingested arsenic. Millions of people worldwide are exposed to arsenic in their drinking water, and recent evidence suggests that these exposures may lead to substantial risks of lung cancer. Currently, little is known about the human toxicokinetics or pulmonary toxicity of ingested arsenic. The candidate proposes three studies in arsenic exposed populations to increase our knowledge of these topics. The first will assess the role of 13 dietary and metabolic factors in arsenic methylation, the primary detoxification pathway of inorganic arsenic. Serum levels of these factors will be compared to arsenic methylation patterns based on the urinary excretion of arsenic metabolites. Previous studies have shown that individuals vary greatly in the degree they methylate arsenic, thus investigating factors that regulate methylation may allow susceptible sub- populations to be identified, and therefore may provide information useful in drinking water regulation. The second study is a cross-sectional cadaver study on the intracellular distribution of arsenic and its metabolites in human tissues. Tissue samples from the six organs will be collected from 20 subjects during routine autopsies performed by the coroners offices of arsenic exposed and unexposed population. The levels of arsenic and its metabolites will be determined in the subcellular components of each organ. Identifying specific patterns of arsenic accumulation may further support the hypothesis that ingested arsenic is a potent lung carcinogen, and may explain why the lung appears more susceptible to arsenic than other tissues. In addition, providing information on the distribution patterns of specific metabolites, particularly monomethylarsonous acid, may add new insight into the role of methylation in arsenic carcinogenesis. The final project is the design of an epidemiological study of lung cancer and low exposures of drinking water arsenic. Currently, little information is available on the cancer effects of arsenic at doses below 100 ug/L. This project will involve the development of all major aspects of study design and implementation with the ultimate goal of preparing an investigation that will provide dose-response data useful in drinking water regulation.